Hypoxic injury in neonates and young children is one of the most prevalent and important types of injury in these age groups. Precise knowledge of how hypoxia leads to tissue injury and the permanent sequelae of hypoxia will provide strategies for therapeutic intervention. Hypoxic-ischemic injury sets up a cascade of events that ordinarily lead to delayed cell death. These events include excitotoxicity, abnormal calcium homeostasis, increased release of free radicals, activation of caspases and other proteases, failure of mitochondrial membrane integrity, all of which may lead to apoptosis or necrosis. Gender has been shown to be a factor determining outcome in focal ischemia and hypoxia-ischemia. We will examine the effects of gender and perturbation of NF-kappaB activity and of IL-1 inhibition with IL-1 receptor antagonist on elements of the immune response, free radical release, ICAM expression, phagocyte recruitment, microvascular function and tissue injury in neonatal hypoxia-ischemia in rats of both genders treated with and without high inspired oxygen in the recovery period. We will measure cytokine mRNA and cytokine protein levels, NF-kappaB nuclear translocation, superoxide production, tissue oxygen levels, regional cerebral blood flow, and tissue injury with and without treatment with SN50, oligonucleotide decoys that specifically inhibit NF-kappaB, or with IL-1 receptor antagonist at various survival intervals. The resulting data will provide insight concerning possible means of limiting tissue injury and of improving outcomes in neonatal hypoxia and ischemia as well as providing basic insights concerning the pathogenesis of this injury.